ZNF32 promotes the self-renewal of colorectal cancer cells by regulating the LEPR-STAT3 signaling pathway

Jun Li,Chunfen Mo,Xiangsheng Fu,Xiaoan Li,Xuemei Li,Yan Zhou,Yan Tian,Lin Sun,Tongqin Zhang,Lili Lan,Yaqi Li

doi:10.1038/s41419-022-04530-4

Jun Li, Chunfen Mo + Show 9 more

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https://doi.org/10.1038/s41419-022-04530-4

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Due to the self-renewal characteristics and tumorigenic abilities of cancer stem cells (CSCs), CSCs have been demonstrated to play vital roles in carcinogenesis and antitumor therapy. Our previous report found that Krüppel-like family members (KLFs) and zinc finger protein 32 (ZNF32) play oncogenic roles in carcinogenesis. However, the roles and mechanism of ZNF32 in CSCs are still unknown. Our study demonstrated that ZNF32 was highly expressed in colorectal CSCs, which promoted their self-renewal capacity and tumorigenicity. Overexpression of ZNF32 in colorectal cancer (CRC) cells increased their self-renewal capacity. Furthermore, we identified the leptin receptor (LEPR) as the downstream target gene of ZNF32 and verified that the ZNF32-mediated regulation of CRC self-renewal is achieved via the LEPR- signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, ZNF32 regulated the expression of SOX2, a core transcription factor in stem cells. Finally, we demonstrated that ZNF32 and LEPR were positively correlated in CRC tissues. ZNF32 expression was negatively correlated with the prognosis of CRC patients. Therefore, therapeutically targeting the ZNF32-LEPR-STAT3 pathway in the clinic is tempting.

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Colorectal cancer (CRC) was the second leading cause of cancerrelated death worldwide in 2018, with an incidence rate of 10.2% and a mortality rate of 9.2% [1]
We found that zinc finger protein 32 (ZNF32) was significantly upregulated in CSCSW480, cancer stem cells (CSCs)-SW620, CSC-pCRC1, and CSC-pCRC2 compared to bulk cells (Figs. 1A and S3B), implying that ZNF32 may play some regulatory roles in colorectal CSCs
Our study showed that sh-ZNF32 significantly reduced the RESULTS Reduced expression of ZNF32 in colorectal CSCs inhibited their self-renewal ability Colorectal CSCs were enriched by serum-free suspension culture (Fig. S1A)

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Introduction

Colorectal cancer (CRC) was the second leading cause of cancerrelated death worldwide in 2018, with an incidence rate of 10.2% and a mortality rate of 9.2% [1]. CSCs have been identified in other hematological malignancies and a variety of solid tumors [5,6,7,8,9,10,11]. Due to their inherent self-renewal characteristics and tumorigenic abilities, CSCs have been demonstrated to play vital roles in tumor development, metastasis, reoccurrence, and resistance to antitumor therapies [3, 12]. We and others have identified various signaling pathways that are involved in the regulation of CSCs, including Wnt, NF-κB, Notch, Hedgehog, JAKSTAT, PI3K/AKT/mTOR, and TGF/SMAD [13]

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